Discovery of 2-(2-aminopyrimidin-5-yl)-4-morpholino-N-(pyridin-3-yl)quinazolin-7-amines as novel PI3K/mTOR inhibitors and anticancer agents

Wei Peng; Zheng-Chao Tu; Zi-Jie Long; Quentin Liu; Gui Lu

doi:10.1016/j.ejmech.2015.11.038

Discovery of 2-(2-aminopyrimidin-5-yl)-4-morpholino-N-(pyridin-3-yl)quinazolin-7-amines as novel PI3K/mTOR inhibitors and anticancer agents

Eur J Med Chem. 2016 Jan 27:108:644-654. doi: 10.1016/j.ejmech.2015.11.038. Epub 2015 Dec 2.

Authors

Wei Peng¹, Zheng-Chao Tu², Zi-Jie Long³, Quentin Liu³, Gui Lu⁴

Affiliations

¹ Institute of Drug Synthesis and Pharmaceutical Process, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, PR China.
² Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, PR China.
³ State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-sen University, Guangzhou 510060, PR China.
⁴ Institute of Drug Synthesis and Pharmaceutical Process, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, PR China; Institute of Human Virology, Sun Yat-sen University, Guangzhou 510080, PR China. Electronic address: lugui@mail.sysu.edu.cn.

PMID: 26731167
DOI: 10.1016/j.ejmech.2015.11.038

Abstract

In this study, a series of novel 7 or 8-substituted 4-morpholine-quinazoline derivatives was designed and synthesized. Their PI3Kα inhibitory activities, antiproliferative activities against seven cancer cell lines, namely, PC-3, DU145, MCF-7, BT474, SK-BR-3, U937 and A431, were evaluated in vitro. Compound 17f proved to be a potential drug candidate with high PI3Kα inhibition activity (IC50 = 4.2 nM) and good antiproliferative activity. Compound 17f was also tested for its inhibitory activities against other kinases, such as PI3Kβ, PI3Kγ, PI3Kδ and mTOR, its effects on p-Akt (S473) and cell cycle. These results suggested that compound 17f could significantly inhibit the PI3K/Akt/mTOR pathway as a potent PI3K inhibitor and anticancer agent.

Keywords: 4-Morpholine-quinazolines; Antiproliferative effects; Kinase inhibitor; Phosphoinositide 3-kinase (PI3K).

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Cell Cycle / drug effects
Cell Line, Tumor
Cell Proliferation / drug effects
Dose-Response Relationship, Drug
Drug Discovery*
Drug Screening Assays, Antitumor
Humans
Molecular Structure
Morpholines / chemical synthesis
Morpholines / chemistry
Morpholines / pharmacology*
Phosphatidylinositol 3-Kinases / metabolism
Phosphoinositide-3 Kinase Inhibitors*
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Proto-Oncogene Proteins c-akt / antagonists & inhibitors*
Proto-Oncogene Proteins c-akt / metabolism
Quinolines / chemical synthesis
Quinolines / chemistry
Quinolines / pharmacology*
Signal Transduction / drug effects
Structure-Activity Relationship
TOR Serine-Threonine Kinases / antagonists & inhibitors*
TOR Serine-Threonine Kinases / metabolism

Substances

2-(2-aminopyrimidin-5-yl)-4-morpholino-N-(pyridin-3-yl)quinazolin-7-amine
Antineoplastic Agents
Morpholines
Phosphoinositide-3 Kinase Inhibitors
Protein Kinase Inhibitors
Quinolines
Proto-Oncogene Proteins c-akt
TOR Serine-Threonine Kinases